This invention relates to mono or di-substituted lower alkyl diether prostaglandins of Formula 1 as follows: ##STR3## WHEREIN: R.sub.1 is hydrogen or lower alkyl;
R.sub.2 is hydrogen when R.sub.6 is hydrogen and Y is a single bond, and R.sub.2 is absent when R.sub.6 is absent and Y is a double bond; PA1 R.sub.3 is keto group, ##STR4## R.sub.4 is hydrogen or ##STR5## R.sub.5 is hydrogen, ##STR6## R.sub.7 is ##STR7## R.sub.8 is hydrogen or ##STR8## R'.sub.9 is hydrogen or lower alkyl; R'.sub.10 is lower alkyl; PA1 R'.sub.11 is lower alkyl; PA1 Z.sub.1 is an unsaturated carbon carbon cis or trans --CH.dbd.CH--; or a saturated --CH.sub.2 CH.sub.2 -- group; PA1 Z.sub.2 is an unsaturated carbon carbon trans --CH.dbd.CH--; or a saturated --CH.sub.2 CH.sub.2 -- group; PA1 X is a carbon carbon covalent bond or it is a carbon carbon covalent double bond with the proviso as set forth for R.sub.4 and R.sub.5 above; PA1 Y is a carbon carbon covalent bond or it is a carbon carbon double bond with the proviso as set forth for R.sub.2 and R.sub.6 above; PA1 n is 1 to 5 and m is 0 to 4; and the non-toxic salts thereof.
The term lower alkyl appearing above and elsewhere in the specification and claims denotes the straight and branched chain lower alkyl hydrocarbon groups of 1 to 8 carbon atoms inclusive, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, pentyl, neopentyl, n-hexyl, isohexyl, heptyl and the like.
The term lower alkoxy appearing in the instant specification denotes straight and branched chain lower alkoxy hydrocarbon groups of 1 to 8 carbon atoms inclusive, such as methoxy, ethoxy, n-propoxy, butoxy, sec-butoxy, amoxy, iso-amoxy, hexyoxy, iso-butoxy, iso-propoxy, and the like.
The phrases pharmaceutically acceptable and non-toxic salts as embraced by the above Formulae and elsewhere in the disclosure and the accompanying claims includes the non-toxic alkali metal and the non-toxic alkaline earth metal bases such as sodium, potassium, copper, magnesium and the like, the hydroxides and carbonates thereof, the ammonium salts and substituted ammonium salts, for example, the non-toxic salts of trialkylamines such as triethylamine, trimethylamine and tri-isopropylamine, and other amines such as morpholine, diethylamine, dimethylamine, methylcyclohexylamine, glucosamine, procaine, dibenzylamine, triethanolamine, N-benzyl-.beta.-phenylethylamine, ethyldimethylamine, benzylamine, N-(lower) alkyl piperidines, such as N-ethylpiperidine, N-methylpiperidine and other pharmaceutically acceptable amines. Also, non-toxic salts with monoalkyl and dialkylamines, and aralkylamines salts formed with compounds of Formula 1 (R.sub.1 =H) and tetra-alkylammonium hydroxides. The latter are generally called therapeutically acceptable quaternary ammonium salts, for example, tetramethylammonium, tetrapropylammonium, tetra-ethylammonium, phenyltriethylammonium, benzyltri-isopropylammonium salts, and the like.
The term "lower alkyl diether" as used herein denotes a lower alkyl substituted ether group of the formula ##STR9## as covalently bonded to the prostaglandin backbone. The lower alkyl diether group is attached to the prostaglandin through an ether-carbon structure ##STR10## that may be conveniently named "methyloxy". The methyloxy group has bonded thereto the groups R'.sub.9, R'.sub.10 and R'.sub.11. The group R'.sub.9 is a hydrogen or lower alkyl group and R'.sub.10 and R'.sub.11 are lower alkyl groups. When R'.sub.9, R'.sub.10 and R'.sub.11 are lower alkyl groups they may be the same or they may be different lower alkyl groups of the straight or branched chain hydrocarbon type of 1 to 8 carbon atoms inclusive, as defined above. The group R'.sub.11 as bonded through the oxygen atom to the carbon atom may also be viewed as a lower alkoxy group. The lower alkoxy group, also an ether, is a straight or branched alkoxy group of 1 to 8 carbon atoms inclusive, as set forth above. Representative of diethers suitable for the present purpose are thus mono or lower dialkyl, lower alkoxy methyloxy groups such as (methyl' methoxy' methyloxy); (methyl' ethyl' methoxy' methyloxy); (ethyl' methyl' propoxy' methyloxy); (diethyl' methoxy' methyloxy); (ethyl' propyl' ethoxy' methyloxy); (dipropyl' ethoxy' methyloxy); (ethyl' iso-propyl' ethoxy' methyloxy) and the like.
The numbering system and the stereochemical nomenclature used for the novel prostaglandin ethers of the invention is the art accepted numbering and nomenclature. That is, the cyclopentane ring of the prostanoic acid is numbered 8 through 12 inclusive, the carboxyl side chain attached to the cyclopentane ring at its 8 position and the alkyl side chain attached to the cyclopentane ring at its 8 position and the alkyl side chain attached to the cyclopentane at its 12 position. When longer or shorter side chains are used, the carboxyl position is numbered as 1 and the numbers increased or decreased throughout the compound to correspond to the length of the chains and the ring inclusive. The stereochemistry of the substituents on the 5-membered cyclopentane ring may be .alpha.-oriented or .beta.-oriented as indicated by a wavy line; the dashed line indicates an .alpha.-orientation and the solid wedged line indicates a .beta.-orientation. Alpha-substituents are oriented on the opposite side of the cyclopentane ring as the .omega.-terminal chain, and .beta.-substituents are oriented in the opposite sense; that is, on the same side as the alkyl side chain. Also, in the formulae as illustrated herein the substituents at positions R.sub.3, R.sub.4, R.sub.5, and the like, as graphically depicted by ##STR11## and the like, indicate that both groups, for example, hydrogen and hydroxyl, are bonded to the carbon atom of the cyclopentane ring. The substituents attached to the alkyl side chain may have a sinister (S) or rectus (R) configuration which for these compounds in the projection shown, is the equivalent nomenclature of .alpha. and .beta. respectively. The diether prostaglandins depicted in the specification and accompanying claims thus includes the analogues and all the diastereomers thereof, and in addition, the enantiomeric forms and such mixtures as are designated racemates. The numbering system and the stereochemistry nomenclature is disclosed and described in Progress In The Chemistry of Fats and Other Lipids, Vol. IX, Part 2, pages 233 to 236, 1968, Pergamon Press, New York, and in J. Lipid Research, Vol. 10, pages 316 to 319, 1969.